Stable anti-hemorrhagic powders



STABLE ANTI-HEMORRHAGIC POWDERS 7 George Madison Sieger and Ernest Chu Yen, Pearl River, N.Y., assignors to American Cyanamid Company, New York, N.Y., a corporation of Maine N6 Drawing. Filed July 26, 1956, Ser. No. 600,166

s Claims. Cl. 167-81) This invention relates to anti-hemorrhagic compositions, and more particularly it relates to dry, stable, substantially non-dusting powders containing water insoluble anti-hemorrhagic compounds.

A numberof anti-hemorrhagic compounds of the vitamin K type have been found to be useful in the prevention and treatment of hypoprothrombinemia, hemorrhagic diathesis of the newly born, in the treatment of post operative bleeding, in jaundice, orin persons having prothrombin deficiencies.

a In the past, these substances have been administered orally or parenterally in solutions of fixed oils 'such as olive oil, sesame oil, peanut oil, etc. Alternately, water soluble salts of these-vitamin K compounds have been used for parenteralinjection. The vitamin K type compounds-are generally unstable to light. The oil solutions proposed in the past have not imparted to these compounds any substantial increased stability to light. Moreover, the rate of absorption of the vitamin K type compounds from oil solutions is retarded somewhat. The

aqueous solutions of salts are somewhat more desirable than the oil solutions, but have the disadvantages that atent O 2,949,400 Patented Aug. 16, 1960 ice Suitable esters for preparing the powders of the present invention include the ethyl and butyl esters of certain dicarboxylic, acids, namely, succinic and pimelic. Any of the water-insoluble substances possessing vitamin K activity can be used in this invention; these anti-hemorrhagic compounds include: 2-methyl-3-phytyl-1,4-naphthoquinone, 2-methyl-1,4-naphthoquinone, 2-methyl-3-hydroxy-1,4-naphthoquinone, 2-methyl 1,4 naphthohydroquinone, dimethoxynaphthalene, 2,3-diine'thyl-l,4-naphthoquinone, 4amino-2-methyl-Lnaphthol, Z-methyl-lnaphthol, Z-methyl-l-nap'hthylamine, 2-methyl-l,4-naph thoquinone-2,3-oxide and esters of the same.

The first mentioned compound above is natural vitamin K and the remainder'of the compounds, for the most part, are vitamin K analogs. One of the simplest members of this series of anti-hemorrhagic substances is menadione (2-methyl-1,4-naphthoquinone), it is the preferred substance for preparing the compositions of the present invention because of its outstanding anti-hemorrhagic action. i

The silica aerogels of this invention are any of a number of commercially available aerogels produced either in the vapor phase or in the liquid phase. The most important characteristic of these aerogels is their extremelylarge surface area; this may run between 100 to 400 square meters/gram. These silica aerogels are dry,

' highly porous powders having a-particle size of from the salts are not always equivalent in activity to that of the parent substance, and furthermore, some of the antihemorrhagic compounds do not form water soluble salts. Moreover, as to the oil solutions, the oils are, of course, subject to becoming rancid, thus producing disagreeable odors. Of more importance in this regard is the fact that when the oils become rancid, they apparently contribute to the decomposition of the vitamin K type compounds. In spite of these disadvantages, the common products found on the market incorporating vitamin K type compounds are generally found in an oil solution. These oil solutions present several other problems. The more common vitamin K type compound, menadione, is soluble in most vegetable oils to the extent of only about 2% w./v. As a result of this a very large volume of the oil solution must be utilized in order to produce a composition in a dosage unit form that contains a sufiicient quantity of menadione to adequately accomplish the purpose for which it is intended. Various other proposals have been set forth in an attempt to overcome these disadvantages, but up to the present. timenone have been proposed which adequately answer the problems presented.

For whether the vitamin K type compound be used per se or in an oil solution, or in some other composition, none of these preparations have very good heat stability.

' It has now been found that the various water-insoluble anti-hemorrhagic compounds can be dissolved in certain organic esters and absorbed on certain solid silica aerogel earriers to producea dry, substantially white, substantially non-dusting, free-flowing powder, the anti-hemorrhagic activity of which is substantially greater per unit volume than any of the known preparations. Moreover, the water-insoluble anti-hemorrhagic compounds are substantially more stable to heat, light, air-oxidation, and decomposition in these powder compositions than in known preparations.

about 5 millimicrons to about 5 microns.v They contain somewhere between 85% and 98% silica, the remainder being made up of various organic and inorganicconstituents. The silica may be present as silicon dioxide,

silicic acid, or silicic acid salts such as calcium silicate. The silica is the only important constituent of the silica aerogel; as long as the other constituents are non-toxic, their identity is immaterial.

The anti-hemorrhagic compounds are sufliciently solue ble in the esters herein utilized to produce a composition containing 4 to 5 times as much of these compounds on an activity basis as those known in the prior art; for example, men-adione (2-methyl-1,4-n'aphthoquinone) has a solubility in diethyl succinate of about 12% w./v., whereas in oils its solubility is about 2% w./v. When compared with other known preparations containing vitamin K type compounds, the powder compositions of this invention exhibit other substantial advantages. Powders of-menadione per se and the othervitamin K type compounds are extremely dusty powders which are very irritating to the skin and. mucous membranes, particularly the tissues of and surrounding the eye, nose, mouth and respiratory passages. 'When the vitamin K type compounds are compounded with the esters and the silica aerogels of this invention, this problem is substantially overcome. Therefore, the powder compositions of this invention permit safer and more expeditious handling in production operations. tion are white free-flowing powders .comparedto the yellow color of menadione powder per se. In many pharmaceutical preparations a white powder is preferred.

The vitamin K type compounds are decomposed by sunlight and are destroyed by alkalies and reducing agents. The compositions of this invention afford these vitamin K type compounds a greater degree of stability in the presence of the decomposing conditions described above. Furthermore, the components of the compositions of the invention afford protective action in minimizing reaction of the vitamin K type compounds with other materials with which they may be compounded, for example, those in a multi-vitamin preparation. Moreover, in general, preparations of vitamin K type compounds do not have long term stability, particularly in the presence of heat. However, it will be shown below that when a solution of one of the vitamin K type compounds is absorbed on The compositions of this invenone of the silica aerogels of this invention, improved heat stability results. Other advantages of the compositions of this invention over those of the prior art will be apparent from the examples and tables that follow.

in preparing the compositions or this invention, it is essential that the menadione or other vitamin K type compound be uniformly distributed throughout the silica aerogel. The simplest method by which end can be obtained is to dissolve the menadione or other vitamin K type compound in one ofthe above described esters and then mix the solution of the vitamin K type compound dissolved in the ester with the desired quantity of the silica aerogel. Alternately, one can mix the proper proportions of all three components simultaneously and by careful and thoroughnlixing achieve the uniformly dispersed condition desired.

As indicated above, menadione has a solubility of about 12% w./v. in diethyl succinate (10 to 11% w./w.). This, therefore, the upper limit or the amount of menadione it is possible to incorporate into the compositions of this invention. There is no theoretical lower limit, only one of practicality. This solution of menadione, or other similar solutions of vitamin K type compounds of the same concentration, or of lesser concentrations, is then mixed with a quantity of the silica aerogel. The upper limit of the amount of the solution of the vitamin K type compound utilized is about 4 parts by weight of the vitamin K type compound solution to 1 part by weight of the silica aerogel. Obviously, any ratio smaller than this can be used as the 4:1 ratio described above produces a dry, free flowin'g powder. As a matter of fact, a ratio of 2:1 is preferred for the purposes of this invention. If the amount of the solutioni's increased substantially beyond 4 parts by'weight to 1 part by weight of the silica aerogel, the composition, on standing, will not remain a free flowing powder. On the contrary, it will become sticky and tend to agglomerate. I

The following examples are set forth in an illustrative sense only, in no way to be'considered as limiting, the scope of the invention being limited by the scope of the appended claims.

EXAMPLE 1 The following solutions ofrnenadion'eand diethyl succinate were formulated (a) 11 grams of menadione in 89 grams of diethyl succinate,(b) 8 grams of menadione in 92 grams of diethyl succinate, (c) *6 grains 'of menadione in94 grams'ofdiethyl succinate. A 20g. portion of each of the above solutions was'mix ed with thorough agitation with a 10 g. portion ofeach of the following silica 'aerogels: ('1) a silica aerogel having a particle of from about 3 to about microns and a surface area of approximately 110 to about 150 square meters/gram, (2) a silica aerogel having a particle size of from about 15 to about 20 millimicrons and asurface area of from about 175 to about 200 square meters/ gram, (3) a silica aerogel having "a particle size of from about 50 to about 100 millimicrons and a surface area of about 200 square meters/ gram, (4) a silica-aerogel having a particle size of about 100 millimicrons and a surface area of about 200 squaremeters/gram (silica as calcium silicate), (5) a silica aerogel having a particle size of from about '8 to about millimicrons and a surface area of from about 285 to about 335 square meters/ gram. Each of the above mixtures of the respective menadione-diethyl succinate solutions with their respective silica aerogels formsa substantially white, substantially dry, free-flowing, substantially'non-dusting powder which contains approximately 7% w./w. of menadione.

EXAMPLE 2 Fifteen multi-vit amin preparations were'fo'rmula'ted inoorporating the following quantities'o'f the various vitamins and a 2.5 mg. quantity of menadione from each of the menadione powders prepared in Example 1.

Each of these 15 multi-vitamin preparations contains the following vitamins in the amount indicated:

Thiamine mononitrate (B mg 10 Riboflavin (B mg 10 Niacinamide mg Ascorbic acid mg 300 Pyridoxine HCl (B mg 2 Vitamin B12 *mc'g 4 Folic acid mg... 1.5 Calcium pantothenate mg 20 Vitamin K as menadione -mg 2.5

Each of these 15 preparations was filled in soft shell gelatin capsules. Satisfactory capsules were obtained in each instance, i.e. they wereof the desired elliptical shape; they sealed properly; they were not discolored; they had no unpleasant odor, and they were of the desired potency. After storage, they exhibited the required potency; there was no gas or odor formation, bacterial growth, or shell destruction or distortion.

EXAMPLE 3 The procedure (if Example -1 was repeated utilizing the same solutions 6f menadione in the quantities indicated in Example -1, however, di-n-butyl 'succinate was substituted for diethyl succinate. The identity and quantity of the silica aerogels utilized in the procedure of this example was the same as in Example 1. Results were obtained herein which were substantially'identical to those obtained'in Example 1.

EXAMPLE 4 The'procedure of Example 1 was repeated utilizing menadione and diethyl succinate in the same quantities as in Example 1. 20 g. of each'of the 3 solutions thereby produced was mixed with thorough agitation with 5 g. of each of the'5 silica aerogels of Example 1. Each of the 15 powders thereby produced was substantially white, dry, free-flowing, and substantially non-dusting.

EXAMPLE 5 The procedure of Example 1 was repeated utilizing the same quantities of menadione and the ester; however, diethyl pi'melate was substituted for the diethyl succinate of Example 1. The same quantities of each of the resulting solutions were formulated with thesame silica aerogels in the same quantities as in Example 1. A substantially white, dry, substantially non-dusting, free-flowing powder'resulted in each instance.

EXAMPLE 6 Theprocedure of Example 1 was repeated utilizing the same quantities of menadione and'the ester;l1owever, din-butyl pimelate was substituted for the diethyl succinate of Example 1. The same quantities of each of the resulti'n'gsolutio-ns were formulated'with'th'e samesilica aerogel in the same quantities as in'EXample 1. A substantially white, substantially non-dusting,free-flowing dry powder resulted in each instance.

EXAMPLE 7 The procedure of Example 1 was repeated utilizing the same ester and silica aerogel in the same quantities. However, 2-methyl-1,4-naphthoh'ydroquinone was substituted for the menadione in the same quantity as found in Example 1. Each of the-fifteen powders thereby 'pro duced was dry and freeflowing, 'and substantially white and non-dusting.

EXAMPLES The procedure of Example l'was repeated utilizing the sameester 'and silica aerogel in'the same quantities. However, '2-methyl-l,4-naphthoquinone=2,3 oxide was substituted for the menadione inthe same quantities as found in Example '1. Each"of',the'fifteen' powders'thereby produced was dry and free-flowing and substantian white and non-dusting.

5 EXAMPLE 9 Chick bioassays were run utilizing a capillary tubewhole blood clotting time method patterned after the procedure found at pages 156 through 158 of Vitamin Methods, volume II (1951), by P. Gyorgy, published by Academic Press. These bioassays compare the efiicacy of the menadione-diethylsuccinate-silica aerogel of Example 1 [(a) and 1)] with other preparations of vitamin K type compounds in the multi-vitamin preparation of Example 2. The results of these bioassay determinations are set forth in the following table.

Table I Menadioue Potency Found by Chick Initial Concentration ofMenadlone Bioassay after 5 Weeks Menadione Composition in Multivitamin Mix At C. At 42 0.

Menadione Powder 2.5 nag/550 mg. Mix 2.50 mg./550 mg... 2.25 ing/550 mg. Menadione Power and Silica Aerogel 2.5 mgj Less than 1.25 1.79 Lug/cap.

mg. cap. Menadione 2,3-Oxtde Powder 2.7 mg./550 mg. Mix equivalent to 1.5 mg./550 mg- Less than 1.25 mg./

2.5 mg. Menadione. 550 mg. Menadione in 11% w./w. Ethyl Succinate 2.5 mg./570 mg. Mix 2.06 mg./570 mg-.. Less [555mm 1.25

mg. mg. Msenaiiorie in Ethyl Succinate Absorbed on 2.5 mg./550 mg. Mix. 2.5 mg./55O mg.. 2.45 mg./550 mg.

an ace 1 A composition of the following w./w. percentage composition:

Percent Menarlinnn 16, 67 Silica Aerogel of Example 1 (1) 33. 33 Alain 1. 00 Glycerine 0. 05 Ethanol- 2.00 Sodium benzoate. 0. 05 Distilled water 46. 90

The data in the foregoing table indicate that, of the preparations tested, only the compositions of this invention are heat stable after storage for 5 weeks at elevated temperatures. They indicate further that only the compositions of this invention and menadione powder per so are stable after storage for 5 weeks at room temperature (20 C.). Of particular interest are the data showing that neither the combination of menadione and the silica aerogel nor the combination of menadione and the ester are stable at either 20 C. or 42 (2., whereas unexpectedly the combination of menadione, the ester and the silica aerogel are stable at both of these temperatures.

The foregoing examples illustrate one use of the compositions of this invention, i.e. oral multi-vitamin preparations. Obviously, the compositions of this invention have many other uses which will be apparent to those skilled in the art, e.g. oral and parenteral administration of menadione in and of itself, and in combination with other substances, i.e. medicaments, vitamins, nutrients and nutritional factors.

We claim:

1. A dry, free-flowing, substantially non-dusting powder comprising a water-insoluble anti-hemorrhagic compound having vitamin K activity, an ester selected from the group consisting of diethyl succinate, di-nbutyl succinate, diethyl pimelate, and din-butyl pimelate, and a silica aerogel having a surface area of from about 100 to about 400 square meters/gram, said water insoluble anti-hemorrhagic compound being in solution in said ester and uniformly distributed in and throughout said silica aerogel.

2. The powder of claim 1 wherein the particle size of said silica aerogel is between about 5 millimicrons and about 5 microns.

3. The powder of claim 2 wherein said anti-hemorrhagic compound is 2-methyl-1,4-naphthoquinone and said ester is diethyl succinate.

4. The powder of claim 3 where n sa d SiliQfl a g l 8. The powder of claim 2 wherein said ester is di-nbutyl succinate.

9. The powder of claim 2 wherein said ester is diethyl pimelate.

10. The powder of claim 2 wherein said ester is di-nbutyl pimelate.

11. The powder of claim 2 wherein said silica aerogel has a particle size of from about 15 to about 20 millimicrons and a surface area of from about 175 to about 200 square meters/ gram.

12. The powder of claim 2 wherein said silica aerogel has a particle size of from about 50 to about millimicrons and a surface area of about 200 square meters/ gram.

13. The powder of claim 2 wherein said silica aerogel has a particle size of from about 8 to 10 millimicrons and a surface area of from about 285 to about 335 square meters/ gram.

References Cited in the file of this patent UNITED STATES PATENTS 2,091,202 Hallock Aug. 24, 1937 I 2,093,454 Kistler Sept. 21, 1937 2,257,545 Curtis Sept. 30, 1941 2,295,129 Riegel Sept. 8, 1942 2,354,738 Carlson Aug. 1, 1944 2,542,061 Smith Feb. 20, 1951 2,589,108 Mark Feb. 20, 1952 2,813,123 Valentine Nov. 12, 1957 FOREIGN PATENTS 2,205 Great Britain 1882 348,184 Great Britain May 8, 1931 OTHER REFERENCES Baker: Drug and Cos. Ind., 55:1, July 1944, pp. 45, -119. 

1. A DRY, FREE-FLOWING, SUBSTANTIALLY NON-DUSTING POWDER COMPRISING A WATER-INSOLUBLE ANTI-HEMORRHAGIC COMPOUND HAVING VITAMIN K ACTIVITY, AN ESTER SELECTED FROM THE GROUP CONSISTING OF DIETHYL SUCCINATE, DI-NBUTYL SUCCINATE, DIETHYL PIMELATE, AND DI-N-BUTYL PIMELATE, AND A SILICA AEROGEL HAVING A SURFACE AREA OF FROM ABOUT 100 TO ABOUT 400 SQUARE METERS/GRAM, SAID WATER INSOLUBLE ANTI-HEMORRHAGIC COMPOUND BEING IN SOLUTION IN SAID ESTER AND UNIFORMLY DISTRIBUTED IN AND THROUGHOUT SAID SILICA AEROGEL. 